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Where are doxycycline's anti-inflammatory properties derived from?

Where are doxycycline's anti-inflammatory properties derived from?



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I have been looking at this antibiotic called doxycycline which is used mainly as an antibiotic. It has however some interesting anti-inflammatory properties. Does anyone know where these anti-inflammatory properties come from, chemically?


Doxycyline inhibits iNOS and TNF-alpha expression. It also influences secretion of IL-1beta, IL-8, and TNF-alpha, as well as other inflammatory cytokines.

[These are results collected from multiple systems.]

For appropriate references, see: Leite et al (2011). Anti-inflammatory properties of Doxycycline and Minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmocology.

As for the chemistry of how doxycycline accomplishes these things, I'm afraid I don't know the answer, but hopefully, this gives you a place to start.


Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach

Affiliations Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, Department of Biophysics, Panjab University, Chandigarh, India

Affiliation Department of Biophysics, Panjab University, Chandigarh, India

Affiliation Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Affiliation Department of Biochemistry, Panjab University, Chandigarh, India

Affiliation Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India


Introduction

CF is characterized by a chronic cycle of airway obstruction, infection and inflammation. The inflammatory component is mediated by a massive influx of activated neutrophils into the lung compartment. Sputum and bronchoalveolar lavage studies demonstrate elevated concentrations of inflammatory cytokines, chemokines, and proteases [1], [2], [3], [4], [5]. In particular, levels of neutrophil elastase and matrix metalloproteinase-9 are elevated in CF and are correlated with levels of matrix breakdown products (i.e. collagen and elastin). Proteolysis leads to airway remodeling, and contributes to the progressive loss of lung function in CF and thus presents an important therapeutic target [3], [6], [7], [8], [9].

Clinical trials with anti-inflammatory therapies have demonstrated mixed results. Long-term studies of systemic corticosteroids and high-dose ibuprofen demonstrated significant reductions in the rate of pulmonary disease progression however, the potential for serious adverse effects limits the use of these agents [10]. Inhaled corticosteroids demonstrate an improved safety profile however, their use is not associated with improvements in pulmonary function [10]. Oral azithromycin is widely prescribed in patients with CF for its effects on reducing Pseudomonas aeruginosa virulence as well as its immunomodulatory activity [11], [12], [13]. However, a large clinical trial found no difference in CXCL-8 levels and only a small difference in elastase from sputum in patients [14]. These data demonstrate the importance of identifying safe and effective anti-inflammatory therapies for patients with CF.

Doxycycline is a tetracycline antibiotic that exhibits potent immune modulating activities in several disease models. Sub-antibacterial-dose doxycycline (SDD) administered in doses ranging from 10 to 40 mg daily for 4–12 months was well tolerated and led to improvements in the treatment of rosacea, acne, and periodontitis [15], [16]. Inflammatory biomarkers including C-reactive protein and MMP-9 were significantly reduced in patients receiving SDD to prevent acute coronary syndromes. Similarly, doxycycline therapy resulted in a 72% reduction in aortic wall neutrophils in patients undergoing aneurysmal repair [17]. Doxycycline when combined with methotrexate resulted in significant improvement in clinical response in patients with rheumatoid arthritis [18]. Of particular relevance is the improvement in pulmonary function and reduction in C-reactive protein in patients with chronic obstructive pulmonary disease treated with doxycycline in a recent clinical trial [19]. These data indicates doxycycline is safe and effective in the treatment of chronic inflammatory conditions and suggests a potential role in CF.

The aims of this study were to evaluate the anti-inflammatory effect and cytotoxicity of doxycycline in CF bronchial epithelial cells.


Doxycycline in rosacea

Subantimicrobial dose doxycycline

The use of doxycycline in rosacea has been proven in several clinical trials either alone or in combination with other therapies ( Table 2 ). Before the introduction of 40 mg doxycycline monohydrate and its FDA approval in 2006 for the treatment of rosacea, there were several reports using subantimicrobial dose doxycycline hyclate 20 mg (SDD). Previous results of a study of doxycycline hyclate 20 mg twice daily for 6 months in the treatment of acne vulgaris had demonstrated a significant decrease in the clinical signs and symptoms without affecting the skin flora. 35

Table 2

Studies of doxycycline in rosacea

StudyNo of subjectsLength of trialDesignResultsComments
Open-label 24 508 weeksDoxycycline hyclate 20 mg twice daily80% to 100% clearance of inflammatory lesions and a 50% reduction in erythemaNo adverse events reported
Multicenter, randomized, double-blind, placebo-controlled 36 13416 weeksDoxycycline hyclate 20 mg twice daily vs placeboReduced lesion count (P = 0.009), and global severity score (P = 0.034)No adverse events reported
Single-center, randomized, double-blind, placebo-controlled 37 4016 weeksDoxycycline hyclate 20 mg twice daily plus metronidazole 0.75% lotion vs placebo plus metronidazole 0.75% lotion. Metronidazole discontinued in both groups at week 12Reduced lesion count (P < 0.01) at week 12 that was maintained at week 16 after 4 weeks of doxycycline as monotherapy (P < 0.01) and decreased global severity score (P = 0.046)Gastrointestinal events more common in the subantimicrobial-dose doxycycline/metronidazole group (5 vs 2). No cases of photosensitivity or vaginitis reported
Multicenter, randomized double-blind, placebo-controlled 31 57316 weeksDoxycycline 40 mg once daily vs placeboReduced lesion count (P <.001), decreased erythema score (P = 0.017)Adverse events were similar in both groups. No cases of photosensitivity or vaginitis reported
Multicenter, randomized double-blind, placebo-controlled 38 7216 weeksDoxycycline 40 mg plus metronidazole gel 1% once daily vs metronidazole gel 1% and placebo. Metronidazole discontinued at week 12 in both groupsReduced lesion count at week 4 (P = 0.008) and at week 12 (P = 0.002), decreased global severity score (P = 0.01) that was maintained through weeks 12 to 16Improvement receded in the group that received only placebo from week 12 to 16
Multicenter, randomized, double-blind, active-control 39 9116 weeksDoxycyline 40 mg plus metronidazole gel 1% once daily vs doxycycline 100 mg plus metronidazole gel 1% once dailySimilar mean change in inflammatory lesion countAdverse events reported in 26 subjects in the 100 mg group versus 6 subjects in the 40 mg group

The first study that reported the efficacy of SDD in the treatment of rosacea was an open-label study that included 50 patients with all stages of rosacea. 24 Patients were treated with SDD 20 mg twice daily for 8 weeks. After an average of 4 weeks, patients experienced an 80% to 100% clearing in inflammatory lesions and a 50% reduction in erythema. At the end of treatment, there were no reports of gastrointestinal side effects, vaginitis, or photosensitivity.

A multicenter, randomized, double-blind, placebocontrolled, 16-week clinical trial evaluated the use of SDD twice daily versus placebo in 134 patients with moderate rosacea. 36 The assessment at week 16 relative to baseline showed a reduced lesion count (P = 0.009), decreased erythema score (P = 0.082), and global severity score (P = 0.034) in the study group compared with placebo. In the investigator’s global assessment scale (IGA), 13.1% of the study group patients achieved a score of 0 (clear) versus 1.5% of those with placebo (P = 0.014). Another single-center, randomized, double-blind, placebo-controlled trial evaluated the combined effect of SDD 20 mg and metronidazole 0.75% topical lotion in the treatment of moderate-to-severe rosacea. 37 Forty patients were randomized to receive SDD plus metronidaloze twice daily or placebo plus metronidazole twice daily for 12 weeks. SDD or placebo monotherapy continued for 4 weeks after metronidazole was discontinued. Results demonstrated a significant reduction from baseline in the total inflammatory lesion count at week 12 (P < 0.01) that was maintained at week 16, after 4 weeks of SDD as monotherapy (P < 0.01). Secondary endpoints of global severity and erythema were also reduced significantly by the combination treatment. There were no between-group differences observed in adverse events and there were no cases of photosensitivity or vaginitis reported.

Anti-inflammatory dose doxycycline

Anti-inflammatory dose doxycycline (Oracea ® Galderma) refers to a specific 40 mg capsule formulation of doxycycline monohydrate containing 30 mg immediate-release and 10 mg delayed-release beads administered once daily and that is devoid of antibiotic activity. 31 It was approved by the FDA in 2006 and is currently the only doxycyline formulation with FDA approval for the treatment of rosacea. Two phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel-group monotherapy trials evaluated the use of once daily anti-inflammatory dose doxycycline (n = 269) or placebo (n = 268) for 16 weeks in the treatment of moderate to severe rosacea. 31 The mean changes from baseline in total inflammatory lesion count in the active treatment groups were �.8 and 𢄩.5 compared to 𢄥.9 and 𢄤.3 in the placebo arms (P < 0.001). This decrease in lesion count was seen as early as 3 weeks, and there was a progressive continued reduction throughout the entire study period. Also, a statistically significant greater reduction in mean total erythema from baseline was observed in the actively treated group compared with placebo-treated subjects in one pivotal study (P = 0.017). Anti-inflammatory dose doxycycline once daily was well tolerated. The percentage of patients discontinuing therapy because of adverse events was very low in both trials and was similar in both the active treatment and placebo group. Vaginal candidiasis and photosensitivity were not reported in the actively treated patients.

The efficacy of anti-inflammatory dose doxycycline in combination therapy for rosacea has also been reported. In a randomized, multicenter, double-blind, placebo-controlled, 16-week trial, the combined effect of anti-inflammatory dose doxycycline 40 mg and metronidazole gel 1% once daily (n = 36) was compared to placebo capsule and metronidazole gel 1% once daily (n = 36) in adults with mild to moderate rosacea. 38 After 12 weeks, metronidazole was discontinued allowing for comparison of anti-inflammatory dose doxycycline and placebo from week 12 to week 16. At both 4 weeks and 12 weeks assessments, the mean inflammatory lesion reduction from baseline was statistically significant in the anti-inflammatory dose doxycycline and metronidazole study arm (P = 0.008 week 4 and P = 0.002 week 12). From weeks 12 through 16, after discontinuation of metronidazole in both study arms, the improvement noted in the first 12 weeks receded in subjects who received only placebo compared with those subjects receiving only anti-inflammatory dose doxycycline. The results of this study indicate that concurrent use of anti-inflammatory dose doxycycline and metronidazole produces a greater magnitude of inflammatory lesion reduction than metronidazole alone.

Anti-inflammatory dose doxycycline compared with conventional dose doxycycline

When comparing anti-inflammatory dose doxycycline with anti-microbial dose doxycycline, a randomized, multi-center, double-blind, active-control, 16-week trial evaluated the efficacy of anti-inflammatory dose doxycycline (40 mg) and topical metronidazole gel 1% once daily (n = 44) versus conventional dose doxycycline (100 mg) and metronidazole gel 1% once daily (n = 47) in adults with moderate to severe rosacea. 39 The mean change from baseline to week 16 in inflammatory lesion count was similar in both study groups and at all study visits. The mean change in erythema score from baseline was slightly greater at all time points in the 40 mg group. This was statistically significant at week 12 (P < 0.04), but not at week 16. The most frequent adverse events included nausea, headache, influenza, nasopharyngitis, urticaria, diarrhea, esophageal pain, vomiting, abdominal pain, and upper abdominal pain in 32 patients. Of these, 26 subjects were in the 100 mg group and 6 subjects were in the 40 mg group. This study demonstrates that although both anti-inflammatory dose doxycycline (40 mg) and conventional dose doxycycline (100 mg) are effective once-daily treatments for moderate to severe rosacea, a higher incidence of adverse events is associated with the use of the 100 mg dose.

Doxycycline in ocular rosacea

Several nonplacebo-controlled studies have reported improvement in the signs and symptoms of ocular rosacea when treated with tetracycline or its derivatives. The largest restrospective study report described improvement in 98% of 113 patients given either tetracycline 250 mg 4 times daily or doxycycline 100 mg once daily. 40 Other prospective studies have demonstrated that between 87.5% and 100% of the patients have improvement of their symptoms of ocular rosacea after treatment with an initial dose of doxycycline 100 mg daily. 41 – 43 Still, randomized, placebo-controlled studies evaluating the efficacy of doxycycline in ocular rosacea are lacking.

Doxycycline versus macrolides in the treatment of rosacea

The first randomized, open clinical trial evaluating the efficacy macrolides versus doxycycline in the treatment of rosacea was reported in 1997. 44 Patients were randomized to receive clarithromycin 250 mg twice daily for 4 weeks, then 250 mg once daily for four weeks (n = 23) or doxycycline 100 mg twice daily for 4 weeks, then 100 mg once daily for 4 weeks (n = 17). After 8 weeks of treatment, there were no significant differences observed in erythema, telangiectases, or in the number of lesions between the two groups. Still, a faster decrease in lesion count was observed in the clarithromycin group, showing a statistically significant (P π.0005) difference in papules and pustules score between the two groups at weeks 4 and 6. The authors concluded that 6 weeks of clarithomycin treatment are as effective in the treatment of rosacea as 8 weeks of doxycycline treatment.

Another randomized, open clinical trial was performed to observe if azithromycin had an equivalent or superior effect to that produced by doxycycline in the treatment of adult patients with papulopustular rosacea. 45 Patients were randomized to receive azithromycin 500 mg 3 times weekly for 1 month, then 250 mg 3 times weekly for the second month, and 250 mg twice weekly for the third month in the first group (n = 37). The second group received doxycycline 100 mg once daily for 3 months (n = 30). In both treatment groups, the mean inflammatory lesion counts were significantly decreased at the third month (P < 0.001 in both groups), and at the second month post-treatment (P < 0.001 in both groups), when compared to baseline. When the efficacies of the two treatments were compared, there were no significant differences in the percentage of decrease in lesions (P = 0.771) or in the patients’ own assessment (P = 0.965). Adverse effects reported included diarrhea in four patients in the azithromycin group and epigastric burning in two patients in the doxycycline group. Only 2 patients discontinued the study because of adverse events, both of whom were in the azithromycin group. This study demonstrated that both treatments were equally effective in treating inflammatory rosacea and that intermittent azithromycin offers an alternative in the management of patients with rosacea.

Doxycycline versus minocycline

Minocycline is not approved by the FDA for the treatment of rosacea, but it is for the treatment of acne. There are currently no clinical trials that have evaluated the use of minocycline for the treatment of rosacea and due to the lack of clinical evidence comparisons of efficacy with doxycycline cannot be drawn. Minocycline has been used as a successful, long-term therapy for patients with acne vulgaris. Clinical trials of treatment of acne vulgaris with minocycline in doses of 100 mg daily have demonstrated a statistically significant decrease in lesion count when compared with placebo. 46 Still, no statistically significant differences have been demonstrated in clinical trials when comparing minocycline with doxycycline, and investigators have concluded that both are equally effective in the treatment of moderate to moderately severe acne vulgaris. 47 – 49

An extended-release (ER) version of minocycline tablets at a dosage of 1 mg/kg/day (Solodyn ® Medicis Pharmaceutical Corporation) was approved in 2006 for the treatment of moderate-to-severe acne in patients older than 12. 50 Unlike the anti-inflammatory dose of doxycycline 40 mg for rosacea, the ER version of minocycline posses antibiotic activity.


Effects of minocycline on periodontal disease

The pharmacological profile of tetracyclines, which combines anti-microbial with anti-inflammatory and anti-apoptotic properties, makes them suitable for periodontal disease treatment, which is characterized by an inflammatory process in addition to its well-known microbial aetiology (Soory, 2008). At the levels conventionally detected in the plasma and gingival crevicular fluid, minocycline causes a significant stimulation of osteoblastic cells, whereas long-term exposure of these cells to tetracyclines results in a proportional increase in the mineralized bone matrix (Gomes and Fernandes, 2007). These effects are achieved without affecting the survival and protein expression of human gingival fibroblasts, epithelial cells and periodontal ligament fibroblasts (Suzuki et al., 2006). Taken together with their anti-microbial activity, these effects may explain the efficacy, in particular of minocycline, in reducing disease progression and promoting periodontal healing when administered at doses of 100� mg럚y 𢄡 for 7� days (Kirkwood et al., 2007 Basegmez et al., 2011).


3. Human coronaviruses (HCoVs)

3.1. History

The human coronavirus (HCoV) was first characterized in the 1960s [ 35 ]. Tyrell and Bynoe from the Common Cold Unit, England, investigated samples from patients with the common cold and isolated a novel flu-like virus in the 1960s. These viruses were labeled as B814 and were reported as ether sensitive in nature. Initially, they were unable to culture B814 by utilizing the available standard culture techniques. However, in 1965, they were successful in growing B814 in organ cultures [ [35] , [36] , [37] , [38] ]. In 1966, Hamre and Procknow from the University of Chicago isolated and reported the presence of a novel RNA virus associated with respiratory disease. This virus was labeled 229E and it exhibited ether sensitivity like the B814 virus [ 39 ].

The B814 and 229E viruses were characterized using electron microscopy by Almeida and Tyrell. These ether sensitive viruses were reportedly indistinguishable from one another as well as the avian infectious bronchitis virus (IBV) [ 40 ].

These novel viruses along with other morphologically identical animal viruses such as IBV were grouped into a new genus termed 𠇌oronavirus” (Latin word 𠇌orona” meaning 𠇌rown”) in 1968. They were named after the characteristic fringe or crown-like rounded projections on their surface (resembling the solar corona) as observed under an electron microscope [ 41 ]. In 1975, the coronaviruses were clubbed under a novel family of viruses named 𠇌oronaviridae” [ 42 ].

Apart from the aforementioned HCoVs, several other strains of HCoVs have been identified some of these include the HCoV-OC43 (1967), SARS-CoV (2002�), HCoV-NL63 (2004), HCoV-HKU1 (2005), Middle East respiratory syndrome (MERS)-CoV (2012), and SARS-CoV-2 (2019) [ [43] , [44] , [45] ].

The HCoVs such as 229E, OC43, NL63, and HKU1 are known as endemic CoVs. They are commonly found in the human population and are known to cause mild respiratory infections [ 46 ]. However, HCOVs such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are the deadlier viruses that have caused the global outbreak and infected thousands of people worldwide [ 44 ].

Towards the latter end of 2002, the emergence of an infectious virus was reported from the Guangdong province, China. This virus was reported to transmit from human-to-human and was later identified as the SARS-CoV in 2002�. The infected people mostly presented with symptoms such as fever, cough, myalgia, etc. Other symptoms included headache, dyspnea, headache, hypoxemia, vomiting, etc. [ [45] , [46] , [47] , [48] , [49] ]. In some cases, the occurrence of pneumonia and ARDS had also been reported [ 48 ].

In 2012, the emergence of another novel infectious HCoV, later named MERS-CoV, was reported. The first case was reported from Saudi Arabia but soon spread across the Arabian Peninsula [ 50 , 51 ]. Several cases were also reported in Asia, Europe, and Africa [ 52 ]. The transmission of MERS-CoV reportedly occurs via human-to-human as well as dromedary camel-to-human. However, the cases of camel-to-human infection are comparatively less [ 53 ]. Infected people initially exhibit symptoms such as fever, headache, cough, myalgia, etc. However, the disease might progress in severe cases and cause pneumonia, ARDS, septic shock as well as multi-organ failure which can be fatal. Besides, cases of asymptomatic MERS-CoV infection have also been reported [ 44 ].

The recently identified novel coronavirus SARS-CoV-2 belongs to the genera β-coronavirus of the Coronaviridae family [ 54 ]. It reportedly shares 96% and 79.6% sequence identity to the bat CoVRaTG13 and SARS-CoV, respectively [ 8 ].

3.2. Origin and structural features

The coronaviruses (CoVs) are single, positive-strand RNA viruses. Their genome is approximately 26� kb in length [ 44 ]. They belong to the coronaviridae family of the order nidovirales and are categorized into the genera – alpha (α), beta (β), gamma (γ), and delta (δ) coronavirus [ 54 ]. The α- and β-CoVs include both human and animal CoVs. The HCoVs such as 229E, NL63 belong to α-CoV while the OC43, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 belong to the β-CoVs. The γ- and δ-CoVs primarily consists of avian coronaviruses.45.

The viral genome of CoV encodes four important structural proteins. They are - the envelope (E), spike (S), membrane (M), and nucleocapsid (N) proteins [ 54 ]. The E, S, and M proteins are anchored in the lipid bilayer of the viral envelope [ 55 ] The M protein is approximately 25� kDa and gives shape to the virus. The E protein is approximately 8� kDa and promotes viral release. Together, the M and E proteins are associated with the viral assembly. Furthermore, they also facilitate the maturation of viral envelopes [ 56 ]. The N protein is involved in the formation of the nucleocapsid. It binds with the viral genome and plays an essential role in viral packaging [ 55 ]. The S protein (class I fusion protein) is approximately 150 kDa. It is responsible for the characteristic spike-like protrusions on the virus. It comprises S1 and S2 subunits and undergoes cleavage by furin-like protease in the host. The S1 subunit contains a receptor-binding domain (RBD). It binds to the host receptor angiotensin-converting enzyme 2 (ACE2). The S2 subunit of the viral S protein then fuses with the cell membrane of the host. This facilitates viral entry into the host cells [ [56] , [57] , [58] ].

3.3. Mechanism of SARS-CoV-2 entry in cells

Till now, the mechanism of SARS-COV-2 infection is not completely elucidated. Several studies are being conducted globally on SARS-COV-2 to unravel the mechanism of infection and pathogenesis of the novel coronavirus. The β-CoVs - SARS-CoV and SARS-CoV-2 are substantially identical and are considered to infect humans similarly. The S protein contributes substantially to the attachment and fusion of the virus with the host cell. The RBD of the S1 subunit of the viral S protein binds to the host cell receptor which initiates the viral infection.

Studies have reported that SARS-CoV and SARS-CoV-2 utilize the same human ACE2 (hACE2) receptor to attach themselves to the host cells [ 8 ]. The ACE2 receptor is significantly expressed in the type II alveolar, oral mucosal, and nasal epithelial cells [ [59] , [60] , [61] ]. The respiratory airways, cornea, heart, kidneys, etc., also express the ACE2 receptor [ 59 ]. These organs are highly vulnerable and most affected in COVID-19 [ 62 ].

A recent study reported that SARS-CoV-2 has a greater affinity to the hACE2 receptor than SARS-CoV. They further stated that structural alterations in the ACE2-binding ridge of SARS-CoV-2 RBD are responsible for the high affinity towards the hACE2 receptor [ 63 ]. The enzyme furin cleaves the SARS-CoV-2 S protein at the S1/S2 site and exposes the S2 subunit which mediates the fusion of viral and host membranes [ 58 , 64 ]. This cleavage is responsible for the pre-activation of the S protein which promotes the subsequent type II transmembrane serine protease (TMPRSS2)-dependent viral entry into host cells [ 64 ]. The TMPRSS2 is considered significant for the entry of SARS-CoV in the host cell. A broader expression of TMPRSS2 is reported in the nasal cavity, lungs, colon, gall bladder, kidney, prostate, pancreas, heart, etc. Further, the nasal epithelial cells are enriched with TMPRSS2 as well as the ACE2 receptor [ 59 ]. The TMPRSS2 primes the ACE2 receptor-bound viral S protein leading to a conformational change [ 64 , 65 ]. This conformational change activates S protein and facilitates the viral entry into the host cells. Moreover, it also clears the ACE2 receptor [ 58 ].

A study reported that TMPRSS2 is expressed specifically in ACE2 + cell types. Further, they also stated that the expression of proteases such as cathepsin B (Cat B) was observed in 㹰�% of ACE2 + cells. Altogether, their findings implied that SARS-CoV-2 might also utilize alternative pathways for entry [ 59 ]. Similar findings were also reported in another in vitro study which demonstrated that SARS-CoV-2 is dependent on both Cathepsin B/L (CatB/L) and TMPRSS2 for priming and entry into the host cell. Their study showed that inhibition of any one of these proteases leads to partial inhibition of viral entry. This suggested that in the absence of TMPRSS2, the virus may utilize CatB/L for its entry and vice-versa [ 66 ].

Following the entry, SARS-CoV-2 liberates its genomic material (mRNA) in the cytoplasm. It takes over the protein synthesis machinery in the host and translates the mRNA in the nucleus. Besides, it also utilizes the machinery to synthesize viral proteins and subsequently initiates viral replication [ 58 ] ( Fig. 2 ).

Mechanism of SARS-CoV-2 entry in cells. A. Binding of SARS-CoV-2 spike to the host ACE2 receptor. B. Cleavage of SARS-CoV-2 spike by TMPRSS2, membrane fusion, infection, and viral RNA release into the host cell.

Abbreviations: ACE2: Angiotensin converting enzyme-2, NTD: N-terminal domain, RBD: Receptor binding domain, S protein: Spike protein, SARS-CoV-2: Severe Acute Respiratory Coronavirus-2.


Where are doxycycline's anti-inflammatory properties derived from? - Biology

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Novel Anti-Inflammatory Molecule Isolated from Soil-Dwelling Bacterium

About three decades after scientists coined the term ‘hygiene hypothesis’ to suggest that increased exposure to microorganisms could benefit health, an international team of biologists from the United States, the United Kingdom and Hungary has identified an anti-inflammatory lipid in the soil-dwelling bacterium Mycobacterium vaccae that may be responsible.

Mycobacterium vaccae. Image credit: Christopher Lowry, University of Colorado, Boulder.

Professor David Strachan from the London School of Hygiene and Tropical Medicine first proposed the hygiene hypothesis in 1989, suggesting that in our modern, sterile world, lack of exposure to microorganisms in childhood was leading to impaired immune systems and higher rates of allergies and asthma.

Researchers have since refined that theory, suggesting that it is not lack of exposure to disease-causing germs at play, but rather to ‘old friends’ — beneficial microbes in soil and the environment that we have long lived alongside — and that mental health is also impacted.

“The idea is that as humans have moved away from farms and an agricultural or hunter-gatherer existence into cities, we have lost contact with organisms that served to regulate our immune system and suppress inappropriate inflammation,” said Professor Christopher Lowry, from the University of Colorado, Boulder, and the inVIVO Planetary Health of the Worldwide Universities Network.

“That has put us at higher risk for inflammatory disease and stress-related psychiatric disorders.”

In the study, Professor Lowry and colleagues identified, isolated and chemically synthesized a novel lipid called 10(Z)-hexadecenoic acid found in Mycobacterium vaccae.

The scientists also used next-generation sequencing techniques to study how this molecule interacted with macrophages, or immune cells, when the cells were stimulated.

They discovered that inside cells, the lipid acted like a key in a lock, binding to a specific receptor, peroxisome proliferator-activated receptor, and inhibiting a host of key pathways which drive inflammation.

They also found that when cells were pre-treated with the lipid they were more resistant to inflammation when stimulated.

“It seems that these bacteria we co-evolved with have a trick up their sleeve,” Professor Lowry said.

“When they get taken up by immune cells, they release these lipids that bind to this receptor and shut off the inflammatory cascade.”

The researchers have long envisioned developing a ‘stress vaccine’ from Mycobacterium vaccae, which could be given to first responders, soldiers and others in high-stress jobs to help them fend off the psychological damage of stress.

“This is a huge step forward for us because it identifies an active component of the bacteria and the receptor for this active component in the host,” Professor Lowry said.


The Influence of Doxycycline on the Attachment of Fibroblasts to Gelatin-Coated Surfaces and Its Cytotoxicity

Department of Periodontology, School of Dentistry, Hokkaido University, Sapporo, Japan.

Department of Oral Molecular Biology, School of Dentistry, Oregon Health Sciences University, Portland, OR.

Department of Periodontology, School of Dentistry, Hokkaido University, Sapporo, Japan.

Department of Oral Molecular Biology, School of Dentistry, Oregon Health Sciences University, Portland, OR.

Abstract

B ecause of their antimicrobial and anti-inflammatory properties, tetracyclines have been used systemically and locally in the treatment of periodontal disease. This study was done to evaluate the influence of doxycycline (De), a tetracycline, on fibroblast adherence to a protein coated surface and its cytotoxicity. Periodontal ligament derived fibroblasts (PLDFs) were either: 1) preincubated with Dc (0 to 100 μg/ml) and then allowed to adhere to a gelatin-coated surface or 2) adherence was first established and then Dc added to the system. After an appropriate time the number of PLDFs adherent, released, or lysed was estimated by a lactic dehydrogenase (LDH) assay. Preincubation of PLDFs in 25 μg Dc/ml or higher concentrations significantly (P<0.01) reduced the number of adherent cells. Fifty μg Dc/ml and higher doses significantly (P<0.01) increased PLDFs cytotoxicity as measured by LDH release. The same trend was noted if PLDFs were allowed to adhere and then subjected to the drug. Microscopic observation of fluorescein diacetate/propidium iodide-stained cells showed that attached-spread cells pulled in, rounded up, and detached in proportion to the increased dose of Dc and the percentage of red-stained cytotoxic cells rose in a similar manner. The data suggested that Dc can be cytotoxic and may inhibit PLDFs adherence and spread along a substratum. J Periodontol 199364:1219–1224.


Acknowledgments

ADM is supported by a postdoctoral fellowship from the Galician Government (Programa de axuda á etapa posdoutoral, XUGA, GAIN, ED481B 2017/053).

The authors want to thank Dr. Filippo Favretto for his help and advice with the DLS measurements, Patrícia Santos for her help with the SDD western blots.

TFO is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2067/1-390729940, and by SFB1286 (project B8). VP is the recipient of a Thesis scholarship from Association France Parkinson. PPM is supported by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821522 (PD-MitoQUANT this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and Parkinson’s UK). This work also benefited from support by Investissements d’Avenir (ANR-10-IAIHU-06) and the Translational Research Infrastructure for Biotherapies in Neurosciences (ANR-11-INBS-0011-NeurATRIS). This work also was supported by PICT 2015 N° 3201. The study was supported by the São Paulo State Foundation for the Support of Research (FAPESP, Brazil Grant 2014/25029-4). EDB is a recipient of grants from the National Council for Scientific and Technological Development (CNPq, Brazil), CAPES, and the French Committee for the Evaluation of Academic and Scientific Cooperation with Brazil, Grant #848/15). EDB is a CNPq senior research fellow.